Treating cancer with drugs that bind tightly to their target molecules via covalent bonds is not a new concept in drug discovery, but it is gaining momentum. Some companies are trying to improve on this approach by using covalence to address elusive targets. These efforts, at least those that are publicly known, focus on small molecules. Working to bring covalency to biologic therapies, Enlaza Therapeutics has raised $100 million for efforts that include work in one of the hottest areas of cancer drug discovery.
The Series A financing announced Tuesday was led by JP Morgan’s Life Sciences group.
Binding of a drug is a chemical reaction between the drug and its target. Most drug interactions can be characterized by “on-rates” when bound to their targets and “off-rates” when dissociated from them, said Sergio Duron, CEO of La Jolla, Calif.-based Enlaza . Small molecules are cleared from the body relatively quickly, which is why these medications usually need to be taken daily. Protein medications like antibodies last longer, meaning dosing can be done less frequently. These biologics also offer better targeting specificity compared to small molecules.
Enlaza called its covalent biological platform technology “War-Lock.” This technology develops drugs that do not react when circulated in the body. But when they find their target, they are activated by that proximity and cause the molecule to form a covalent bond. The War Lock platform is based on technologies licensed from the University of California, San Francisco and the Scripps Research Institute. Duron said the research involves the use of non-natural amino acids that are not reactive until they are in forced proximity to a target. Research published in the journal Cell in 2020 sparked the idea of applying this strategy to proteins, Duron said.
Unlike small molecules, whose action relies primarily on blocking their targets, Enlaza’s biologics contain therapeutic agents. Enlaza is initially focused on cancer, with its research interests including antibody-drug conjugates (ADCs). These drugs consist of a toxic drug load that is chemically bound to an antibody that delivers the therapy to cancer cells. However, sometimes the amount of active ingredient is released too early, causing unwanted effects elsewhere in the body. One way pharmaceutical companies are trying to improve ADCs is through better linkers.
Using covalence to achieve selective and specific binding to cancer cells could represent another opportunity to improve ADCs. Enlaza aims for high clearance of its drugs so they don’t stick around and cause side effects, Duron said. However, while an Enlaza cancer drug is in the body, it lingers on its target for a long time via the covalent bond.
“This is not just another ADC,” Duron said. “This is a different strategy to approach what is a very, very hot field right now, where everyone is innovating on linker/payload strategies, and we are innovating on a different part of that molecule.”
Enlaza was founded in 2022 with $61 million in seed funding led by Avalon Ventures. This capital was used to translate the science from a scientific paper into a drug development machine. Duron said Enlaza has achieved preclinical proof of concept, demonstrating improved safety and efficacy of its covalent biologics. With the funding, the company will further develop its pipeline with the goal of reaching the clinic. Duron declined to provide a specific timeline, but said he expects “at least some development candidates” to advance to clinical testing in the next few years.
The company is not yet announcing its goals. But Duron said the war-lock approach could be applied to other types of cancer drugs, such as radioligand therapies. As a platform technology, War-Lock also has potential applications in other therapeutic areas, such as autoimmune diseases. Now that the startup has emerged from semi-stealth mode, it is looking for potential partners from the biopharmaceutical industry interested in exploring applications of the technology. Duron said he wants to work with companies “that can advance our pipeline and align with our covalent protein drug vision.”
In addition to JP Morgan, other participants in Enlaza’s new financing include previous investors Frazier Life Sciences, Avalon Ventures, Lightspeed Venture Partners and Samsara BioCapital. The startup’s new investors include Amgen Ventures, Regeneron Ventures, Bregua Corporation, Pappas Capital and Alexandria Venture Investments.
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